Ghalib Mohammad H, Pulla Mariano Provencio, De Miguel Luken Maria J, de Juan Virginia Calvo, Chaudhary Imran, Hammami M Bakri, Vikash Sindhu, Maitra Radhashree, Martinez Sara, Kahatt Carmen, Extremera Sonia, Fudio Salvador, Goel Sanjay
Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA.
Now at Rutgers Cancer Institute, New Brunswick, NJ, USA.
Invest New Drugs. 2024 Oct;42(5):481-491. doi: 10.1007/s10637-024-01458-8. Epub 2024 Aug 3.
Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m/Gem 1000 mg/m) was the MTD. Accrual into DL7 (Plo 10.0 mg/m/Gem 1000 mg/m) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m/Gem 1000 mg/m. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.
普洛卡布ulin（Plo）可诱导微管蛋白纤维解聚，导致微管网络紊乱和碎片化，进而引发有丝分裂。在临床前研究中，Plo与吉西他滨（Gem）联合显示出协同抗肿瘤活性。这项I期试验评估了每3周在第1天和第8天静脉输注10分钟Plo加Gem对晚期实体瘤患者的安全性、药代动力学（PK）和疗效。57名患者入组8个剂量水平（DLs）；74%为女性；74%的东部肿瘤协作组（ECOG）体能状态为1；中位年龄62岁；既往治疗线数中位数为3。第1周期的剂量限制性毒性（DLT）为最大耐受剂量（MTD）时的3级肠梗阻、3级周围感觉神经病变（PSN）、3级腹痛和4级血小板减少（各1例）。最高剂量水平（DL8：Plo 10.5mg/m²/Gem 1000mg/m²）为MTD。在正式确定为推荐剂量（RD）之前，DL7（Plo 10.0mg/m²/Gem 1000mg/m²）的入组被停止。最常见的治疗相关不良事件（AE）为疲劳（56%）、恶心（55%）、腹泻（31%）；3/4级血液学毒性包括贫血（35%）、中性粒细胞减少（27%）和血小板减少（17%）。未发生与治疗相关的死亡。所有剂量水平下Gem或dFdU的PK参数与文献参考值一致。46例可评估患者中有6例缓解（总缓解率：13%）。值得注意的是, 13例卵巢癌患者中有2例部分缓解（PR）和2例疾病稳定（SD）≥4个月。Plo和Gem的联合耐受性良好。MTD为Plo 10.5mg/m²/Gem 1000mg/m²。未发现PK药物相互作用。最令人鼓舞的结果出现在卵巢癌患者中。
